JP5222726B2 - Process for the preparation of racemic alkyl-5-halopent-4-enecarboxylic acids or -carboxylic esters - Google Patents

Description

Detailed Description of the Invention

  The present invention relates to a process for the preparation of racemic alkyl-5-halopent-4-enecarboxylic acids or esters thereof.

  Alkyl-5-halopent-4-enecarboxylic acids and esters thereof are pharmaceuticals such as delta-amino-gamma-hydroxy-omega-arylalkanes which have renin inhibitory properties and can be used in pharmaceutical formulations as antihypertensive agents It is an intermediate useful for the preparation of carboxamides.

  An example of a variant of the preparation of alkyl-5-halopent-4-enecarboxylic acid esters is described in WO 01/09079, according to which a super strong base such as lithium diisopropylamide (LDA) The desired ester is obtained as a racemate in 84% yield by reacting isovaleric ester with 1,3-dihalo-1-propene in the presence of and tert-butoxide (KOtBu).

  A significant drawback of this method is the use of superbases, which necessitates lower reaction temperatures (−15 ° C.). This method cannot be used on an industrial scale for economic reasons because LDA is separately prepared from expensive n-butyllithium.

  J. et al. Agric. Food Chem. 32, No. 1, p. 85-92 disclose, for example, the preparation of various haloalkene carboxylic acids such as racemic 2-isopropyl-5-chloropent-4-ene carboxylic acid starting from the corresponding dialkyl isopropylmalonate. Yes. This malonic ester is first alkylated with 1,3-dichloro-1-propene in the presence of sodium hydride, followed by dealkoxycarboxylation, and the ester is hydrolyzed to give racemic 2-isopropyl- It becomes 5-chloropent-4-enecarboxylic acid. The economic and operational disadvantages of using this on an industrial scale are the use of NaH as a base during alkylation and DMSO as a solvent during dealkoxycarboxylation.

  According to WO 2004/052828 pamphlet, J. Agric. Food Chem. 32, No. 1, 1, p. Some operating conditions of the method according to 85-92 are easily changed. The racemic yield of the corresponding ester is only 75%.

  The object of the present invention is a process for the preparation of racemic alkyl-5-halopent-4-enecarboxylic acids and esters thereof, wherein the desired compound can be prepared in a higher yield than the prior art, economically. The goal was to find a method that was feasible and more environmentally compatible.

（式中、Ｒは、Ｃ_１〜Ｃ_６アルキル基であり、Ｒ_１は、ＨまたはＣ_１〜Ｃ_４アルキルであり、Ｘは、塩素、臭素、またはヨウ素である）のラセミ体アルキル−５−ハロペンタ−４−エンカルボン酸およびそのエステルの調製方法であって、
ａ）式（ＩＩ）

（式中、Ｒは、上記と同義であり、Ｒ_２は、Ｃ_１〜Ｃ_４アルキル基である）のアルキルマロン酸ジアルキルを、式ＭＯＲ_３（式中、Ｍは、Ｎａ、Ｋ、またはＬｉであってもよく、Ｒ_３は、Ｃ_１〜Ｃ_４アルキル基である）の金属アルコキシドの存在下に、有機溶媒中で、１，３−ジハロプロペンと反応させることにより、対応するアリル化マロン酸エステルを得るステップと、次いで、
ｂ）転化完了後、反応混合物に無機塩およびＣ_１〜Ｃ_６アルコールを添加し、この反応混合物を環流温度に加熱するステップと、次いで、
ｃ）抽出または直接蒸留によって所望の式（Ｉ）のラセミ体エステルを単離するステップと、
ｄ）所望の最終生成物がラセミ酸である場合は、エステル官能基を加水分解するステップと
を含む方法を提供するものである。 Accordingly, the present invention provides a compound of formula (I),

(Wherein, R _is C 1 -C ₆ alkyl group, _{R 1} is H or _C 1 -C ₄ alkyl, X is chlorine, bromine, or iodine) racemic alkyl -5 A process for the preparation of halopent-4-enecarboxylic acid and esters thereof,
a) Formula (II)

Wherein R is as defined above and R ₂ is a C ₁ -C ₄ alkyl group, a dialkyl alkyl malonate of formula MOR ₃ (where M is Na, K, or Li Wherein R ₃ is a C ₁ -C ₄ alkyl group) in the presence of a metal alkoxide in an organic solvent to react with the corresponding allylated malonic acid. Obtaining an ester, and then
b) after the conversion is complete, adding an inorganic salt and a C ₁ -C ₆ alcohol to the reaction mixture and heating the reaction mixture to reflux temperature;
c) isolating the desired racemic ester of formula (I) by extraction or direct distillation;
d) if the desired end product is a racemic acid, hydrolyzing the ester functionality.

  The process according to the invention is for the preparation of racemic alkyl-5-halopent-4-enecarboxylic acids of the formula (I) or esters thereof.

In the formula (I), R _is, C 1 -C ₆ alkyl group, e.g., methyl, ethyl, propyl, isopropyl, n-, iso - and tert- butyl, pentyl, and hexyl.

Preferably C ₁ -C ₄ alkyl group, an isopropyl group is particularly preferred.

R ₁ is H in the case of a carboxylic acid, and is a C ₁ -C ₄ alkyl group, preferably a C ₁ -C ₂ alkyl group, more preferably a methyl group in the case of an ester.

  X is chlorine, bromine or iodine, preferably chlorine.

  The preparation of the racemic carboxylic acid of formula (I) or ester thereof of the present invention proceeds in multiple steps.

The first in step a), formula (II) (wherein, R represents the same meaning as above, _{R 2 is} C 1 -C ₄ alkyl group) alkyl malonate dialkyl 1,3 dihalopropene Reacts, i.e. allylated.

  Compounds of formula (II) can be prepared according to the prior art, for example according to WO 2004/052828.

（式中、Ｒ_２は、上記と同義である）の対応するマロン酸ジアルキルを、式ＭＯＲ_３（式中、Ｍは、Ｎａ、Ｋ、またはＬｉであってもよく、Ｒ_３は、Ｃ_１〜Ｃ_４アルキル基である）の金属アルコキシドの存在下に、好適な溶媒中で、式Ｒ−Ｘ（式中、Ｘは、臭素、塩素、ヨウ素であり、Ｒは、上記と同義である）のハロゲン化アルキルと反応させることによって調製される。 The compound of formula (II) is preferably of formula (III),

Wherein R ₂ is as defined above, and the corresponding dialkyl malonate of formula MOR ₃ , wherein M may be Na, K, or Li, and R ₃ is C ₁ in the presence of a metal alkoxide ~C ₄ alkyl group), in a suitable solvent, wherein R-X (wherein, X is bromine, chlorine, iodine, R is as defined above) Prepared by reacting with an alkyl halide of

  The amount of halide used is 0.8 to 1.5 molar equivalents, preferably 1.0 to 1.1 molar equivalents based on the malonic ester of formula (III). Bromide is particularly preferred.

  Similarly, the amount of metal alkoxide used is 0.8 to 1.5 molar equivalents, preferably 1.0 to 1.1 molar equivalents based on the malonic ester of formula (III).

  Suitable solvents include aprotic solvents such as aromatic hydrocarbons (toluene, xylene, benzene, etc.), aliphatic hydrocarbons (hexane, heptane, etc.), aprotic polar solvents such as amides, sulfoxides (DMF, DMA, NMP, DMSO, sulfolane, etc.) and ether (THF, MTBE, etc.).

  It is preferred to use DMF.

  The compound of formula (II) is then isolated by extraction. This compound is preferably purified under reduced pressure by distillation using a column.

  1,3-dihalopropene is added in an amount of 0.8 to 1.5 molar equivalents, preferably 1.0 to 1.1 molar equivalents. It is preferable to use 1,3-dichloropropene.

The reaction is carried out in an organic solvent in the presence of a metal alkoxide of formula MOR ₃ (wherein M may be Na, K, or Li and R ₃ is a C ₁ -C ₄ alkyl group). Will be implemented.

  The amount of metal alkoxide used is 0.6 to 1.3 molar equivalents, preferably 0.9 to 1.1 molar equivalents, based on the malonic ester of formula (II).

  Suitable solvents include aprotic solvents such as aromatic hydrocarbons (toluene, xylene, benzene, etc.), aliphatic hydrocarbons (hexane, heptane, etc.), aprotic polar solvents such as amides, sulfoxides (DMF, DMA, NMP, DMSO, sulfolane etc.), ether (THF, MTBE etc.), DMSO etc.

  It is preferred to use DMF.

  The reaction temperature in step a) is 40-200 ° C, preferably 60-90 ° C.

After completion of the reaction, in step b) (de-alkoxy carboxylation), inorganic salts, for _{example, LiCl, NaCl, CaCl 2,} MgCl 2, NaBr, LiCN, NaCN , etc., preferably, LiCl or CaCl ₂ and _C 1 -C ₆ alcohols, preferably C ₁ -C ₄ alcohols, more preferably methanol are added.

  The amount of inorganic salt added is 0.1 to 1.5 molar equivalents, preferably 0.5 to 0.75 molar equivalents, based on the allylated malonic ester.

  The amount of alcohol added is 0.5 to 3.0 molar equivalents, preferably 0.8 to 1.5 molar equivalents, based on the allylated malonic acid ester.

  The reaction mixture is then heated for a predetermined time at a temperature of 130-180 ° C, preferably 140-145 ° C, when the solvent is DMF.

  The racemic ester of formula (I) is then obtained by extraction or direct distillation.

  If the desired end product is a suitable carboxylic acid of formula (I), hydrolysis of the ester function is carried out by conventional methods, for example by adding NaOH and water, and then the alcohol formed is Distilled. The acid is isolated by extraction.

  By the process according to the invention, starting from the corresponding malonic acid alkyl ester, the racemic alkyl-5-halopent-4-enecarboxylic acid and its esters are higher than the prior art, up to 98% of theory. Obtained at a rate.

  Compared to the prior art, especially as a result of adding alcohol instead of water, the amount of salt required is much less and, in particular, no vigorous gas evolution occurs during dealkoxycarboxylation. It is advantageous.

  The racemic alkyl-5-halopent-4-enecarboxylic acid and its esters prepared according to the present invention are then separated into their enantiomers by conventional methods (eg enzymatic or classical optical resolution). Can do.

[Example 1]
First, 382 g (406 ml) of DMF was charged into Schmizzo, and 137 g (141 ml) of 1.0 equivalent of NaOMe (30% solution in methanol) was added. The mixture was then heated to 60 ° C. (± 3 ° C.) and 131 g (0.753 mol) of dimethyl isopropylmalonate was metered in within 1 hour. The methanol / DMF mixture (201 g) was then distilled off at a temperature of 60 ° C. under pressure (300 mbar-60 mbar). Thereafter, at 80 ° C. (± 3 ° C.), 86 g of 1,3-dichloropropene (79 ml, 0.779 mol, 1.03 eq) were metered in within 1 hour, and then the reaction mixture was heated to 80 ° C. (± 3 ° C. ) For 2 hours.

The reaction mixture was heated to 140 ° C., a 25% solution of LiCl (0.6 eq) in methanol (19 g LiCl in 58 g methanol) was metered in within 2 hours and the reaction mixture was heated at 140-142 ° C. for an additional 6 hours. . Meanwhile, a part of methanol was distilled off, and about 1.5 mol of gas (mainly CH ₃ Cl and CO ₂ ) was formed. The maximum amount of gas in the first 30 minutes was about 6 liters.

  After completion of the reaction, the solvent (DMF) and excess methanol were distilled off substantially completely under reduced pressure. The residue was mixed with 200 g water, 89 g 34% HCl, and 200 g MTBE and the phases were separated. The organic phase was washed once with 50 g of water and the solvent was removed under reduced pressure. About 140 g of product was obtained, of which about 125 g was an ester and 13 g was the corresponding acid.

  The above product was further processed to prepare the corresponding acid. After 140 g of the crude product was suspended in 150 g of water, 70 g (1.15 equivalent) of 50% NaOH was added. The reaction mixture was first charged into an autoclave and heated at a maximum of 3 bar and a temperature of 100-110 ° C. for 2 hours. After completion of the reaction, the formed methanol was distilled off from the top of the column. The pH of the mixture was then adjusted to 1.5 with H2SO4 (76%), extracted twice with 100 g each of IPAT, and the solvent was removed under reduced pressure. 125-127 g of acid (96% of theory) was obtained as a colorless liquid.

[Example 2]
The reactor was charged with dimethylformamide (406 ml, 382 g) and sodium methoxide (140 ml, 136 g, 753 mmol, 30% solution in methanol). The reaction mixture was heated to 60 ° C. Dimethyl isopropylmalonate (127 ml, 131 g, 753 mmol) was metered in within 30 minutes and the methanol was distilled off at a temperature of 69-74 ° C. and a pressure of 330-50 mbar.

  Trans-1,3-dichloropropene (70 ml, 84 g, 753 mmol) was metered in at 80 ° C. within 1 hour and the reaction was stirred at 80 ° C. for 90 minutes.

CaCl ₂ (83.5 g, 753 mmol) was added and the mixture was heated to 140-145 ° C. Methanol was continuously metered in (total 30 ml, 24 g, 742 mmol) while maintaining the reaction temperature at about 140-145 ° C. This suspension was stirred at the same temperature for 12 hours, during which time gas (mainly CH ₃ Cl and CO ₂ ) was formed. The maximum amount of gas in the first 30 minutes was about 6 liters.

  Dimethylformamide (260 ml, 247 g) was distilled off at 70-80 ° C. and pressure (150-25 mbar). The resulting suspension was cooled to 55 ° C. and mixed with 250 g of water, 90 g of HCl (34% aqueous solution), and 190 g of MTBE.

  The phases were separated and the organic phase was washed with 100 g of water. The organic phase thus obtained was treated as follows.

  The organic MTBE phase was concentrated under reduced pressure. Residual MTBE was removed by adding 50 g of water and distilling off the MTBE / water mixture.

Water (135 g) and sodium hydroxide solution (75 g, 49 ml, 50% aqueous solution) were added and the reaction was heated to 105-110 ° C. for 2 hours at a maximum pressure of 3 bar. After completion of the reaction, about 60 ml of MeOH / water mixture was distilled off. Then, the addition of water (135 _g), the pH was adjusted to 3.0 to 4.0 with H ₂ SO 4 (76% aqueous solution). This solution was mixed with isopropyl acetate at 25 ° C. and the phases were separated. The organic phase was washed with 30 g of water and the solvent was removed under reduced pressure. 191 g of racemic acid were obtained as a brown liquid (92% of theory).

The organic MTBE phase was extracted with water (25 g) and sodium hydroxide solution (10 g, 50% aqueous solution) and then washed with water (25 g). The combined aqueous phase contained 17 g of racemic acid (13% of theory). This can be esterified with MeOH and a catalytic amount of H ₂ SO ₄ .

  The organic phase was concentrated under reduced pressure and the residue was distilled at 170-171 ° C. and standard pressure. 113 g of racemic ester were obtained as a colorless liquid (79% of theory).

Claims (8)

Formula (I),

(Wherein, R _is C 1 -C ₆ alkyl group, _{R 1} is H or _C 1 -C ₄ alkyl, X is chlorine, bromine, or iodine) racemic alkyl -5 A process for preparing a halopent-4-enecarboxylic acid or ester thereof,
a) Formula (II),

Wherein R is as defined above and R ₂ is a C ₁ -C ₄ alkyl group, a dialkyl alkyl malonate of formula MOR ₃ (where M is Na, K, or Li And
Reacting with 1,3-dihalopropene in an organic solvent in the presence of a metal alkoxide of R ₃ is a C ₁ -C ₄ alkyl group to obtain the corresponding allylated malonic ester; Then
b) After complete conversion, the steps of the reaction mixture by adding an inorganic salt and C ₁ -C ₆ alcohol, heating the reaction mixture to the reflux temperature, then,
c) isolating the desired racemic ester of formula (I) from the reaction mixture by extraction or direct distillation;
d) if the desired final product is a racemic acid, hydrolyzing the ester functionality, but if the desired final product is a racemic ester, do not perform this step; Including methods.   In step a), the amount of 1,3-dihalopropene is 0.8 to 1.5 molar equivalents and the metal alkoxide is 0.6 to 1.3 mol, based on the malonic ester of formula (II), respectively. 2. A process according to claim 1 used in an equivalent amount.   The process according to claim 1 or 2, wherein the 1,3-dihalopropene used is 1,3-dichloropropene. Step b) is the inorganic salt used _{in, LiCl, CaCl 2, MgCl 2} , NaCl, NaBr, a salt from the group of LiCN or NaCN,, wherein the alcohol used _is in C 1 -C ₄ alcohol The method according to any one of claims 1 to 3, wherein:   In step b), the inorganic salt is used in an amount of 0.1 to 1.5 molar equivalents and the alcohol is used in an amount of 1.0 to 3.0 molar equivalents, respectively, based on the allylated malonic acid ester. The method according to any one of claims 1 to 4. The dialkyl alkyl malonate of formula (II) is first of formula (III),

(Wherein R ₂ is as defined above) and the corresponding dialkyl malonate of formula MOR ₃ (wherein M is Na, K, or Li, and R ₃ is C ₁ -C _4. Halogenation of the formula R—X (wherein X is bromine, chlorine or iodine and R is as defined above) in the presence of a metal alkoxide (which is an alkyl group) in a suitable solvent. Prepared by reacting with alkyl,
It said suitable solvents, Fang aromatic hydrocarbons, alicyclic aliphatic hydrocarbons, selected from the group consisting of aprotic polar solvents and d ether The method of claim 1.   The alkyl halide is used in an amount of 0.8 to 1.5 molar equivalents and the metal alkoxide in an amount of 0.8 to 1.5 molar equivalents, respectively, based on the malonic ester of formula (III). The method according to claim 6.   8. A process according to any one of the preceding claims, wherein the malonic ester of formula (II) is purified by vacuum distillation using a column prior to the reaction with 1,3-dihalopropene.